Abstract
Candida albicans is part of the human gastrointestinal (GI) microbiota. To better understand how C. albicans efficiently establishes GI colonization, we competitively challenged growth of 572 signature‐tagged strains (~10% genome coverage), each conditionally overexpressing a single gene, in the murine gut. We identified CRZ2, a transcription factor whose overexpression and deletion respectively increased and decreased early GI colonization. Using clues from genome‐wide expression and gene‐set enrichment analyses, we found that the optimal activity of Crz2p occurs under hypoxia at 37°C, as evidenced by both phenotypic and transcriptomic analyses following CRZ2 genetic perturbation. Consistent with early colonization of the GI tract, we show that CRZ2 overexpression confers resistance to acidic pH and bile salts, suggesting an adaptation to the upper sections of the gut. Genome‐wide location analyses revealed that Crz2p directly modulates the expression of many mannosyltransferase‐ and cell‐wall protein‐encoding genes, suggesting a link with cell‐wall function. We show that CRZ2 overexpression alters cell‐wall phosphomannan abundance and increases sensitivity to tunicamycin, suggesting a role in protein glycosylation. Our study reflects the powerful use of gene overexpression as a complementary approach to gene deletion to identify relevant biological pathways involved in C. albicans interaction with the host environment.
| Original language | English |
|---|---|
| Article number | 12890 |
| Journal | Cellular Microbiology |
| Volume | 20 |
| Issue number | 11 |
| Early online date | 7 Aug 2018 |
| DOIs | |
| Publication status | Published - Nov 2018 |
Bibliographical note
We are grateful to members of the genomics core facility (PF2, Génopole) for the availability of the microarray scanner and the Alain Jacquier’s lab for making the GenePix software available. We are grateful to Drs. Suzanne Noble and Aaron Mitchell for providing C. albicans mutant collections. We thank all members of the Fungal Biology & Pathogenicity Unit, particularly Drs. Anne Neville and Adeline Feri for their numerous insights during the course of this project. This work has been supported by grants from the Agence Nationale de la Recherche (KANJI, ANR-08-MIE-033-01 to C.d’E. and F.D.; ERA-Net Infect-ERA, FUNCOMPATH, ANR-14-IFEC-0004; and CANDIHUB, ANR-14-CE-0018 to C.d’E.), the French Government’s Investissement d’Avenir program (Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases, ANR-10-LABX-62-IBEID to C.d’E.; Institut de Recherche Technologique BIOASTER, ANR-10-AIRT-03 to C.d’E., F.D. and T.J.), the European Commission (FinSysB PITN-GA-2008-214004 to C.d’E.) and the Wellcome Trust (The Candida albicans ORFeome project, WT088858MA to C.d’E. and C.M.). C.M. acknowledges support from the Medical Research Council, UK (New Investigator Award, G0400284), the MRC Centre for Medical Mycology (MR/N006364/1) and the University of Aberdeen. S.Z. is an Institut Pasteur International Network Affiliate Program Fellow. S.Z., L.v.W. and A.H.C. were the recipients of post-doctoral fellowships from the European Commission (FINSysB, PITN-GA-2008-214004 to S.Z.), the Agence Nationale de la Recherche (KANJI, ANR-08-MIE-033-01 to S.Z.; ERA-Net Infect-ERA, FUNCOMPATH, ANR-14-IFEC-0004 to A.H.C.; CANDIHUB, ANR-14-CE-0018 to L.v.W) and the French Government’s Investissement d’Avenir program (Institut de Recherche Technologique BIOASTER, ANR-10-AIRT-03 to S.Z. and A.H.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Keywords
- Candida albicans
- gastrointestinal colonization
- signature-tagged overexpression
- transcriptomics
- chromatin immunoprecipitation-on-chip
- regulatory networks
- CRZ2
